J. CHEM. SOC. PERKIN TRANS. I 1989 1067 Complex Quinuclidines (1-Azabicyclo[2.2.2]octanes) from Sugars: Synthesis of (1a,3a,4a,5ar)-Quinuclidine-3,5-diol from D-Glucose George W. J. Fleet, Christopher J. Mathews, Julio A. Seijas, and M. P. Vazquez Tat0 Dyson Perrins Laboratory, Oxford University, South Parks Road, Oxford OX 7 3QY David J. Brown Pfizer Central Research, Sandwich, Kent CT 73 9NJ The synthesis of (1a,3a,4a,5a) -quinuclidine-3,5-diol from o-glucose by two alternative ring closures is described. Few strategies have been delineated for the stereocontrolled synthesis of multisubstituted quinuclidines. However, recently two alternative approaches to the enantiospecific synthesis of chiral quinuclidines from sugars have been exemplified in the synthesis of (S)-quinuclidin-3-01 from glu~ose.~,~ The potential of sugars for the synthesis of complex quinuclidines is further illustrated in this paper by the synthesis of the meso-quinuclidinediol (1) from glucose; the accompanying paper reports the synthesis of a chiral quinuclidine diol from arabino~e.~ The azido alcohol (4) is a key divergent intermediate for the synthesis of the meso-quinuclidinediol (1) from D-glucose.Formation of a piperidine ring by closure of the amine derived from the azide onto C-1 of the sugar allows the development of a suitably protected derivative of the amino mesylate (2) from H H D -glucose numbering relates to carbons in glucose which the second six-membered ring may be formed by intra- molecular displacement of mesylate by nitrogen.Alternatively, the first piperidine ring may be obtained by closing the nitrogen function onto C-5 of the sugar, leading to a protected derivative of (3) which is the enantiomer of the amino mesylate (2). The synthesis of (4) from glucose requires the introduction of a two carbon chain with a terminal nitrogen function at C-3 of glucose, followed by degradation of the sugar to remove C-6. Diacetone glucose (1,2;5,6-di-isopropylidene-~-glucose) was converted in six steps as previously described, into the azido diol (5) in an overall yield of 68%. Oxidation of (5)with sodium periodate, followed by reduction of the resulting aldehyde with sodium borohydride in ethanol gave the azido alcohol (4),* m.p.59-62 "C, [a]:' +85.3" (c, 1.0 in CHCl,), in 85% yield. Thus 20 g amounts of the easily crystallised compound (4) may readily be prepared from diacetone glucose in an overall yield of 58%. The piperidine mesylate (2) was prepared by a sequence leading to closure of an azide-derived amine onto C-1 of the sugar. Hydrolysis of the acetonide (4) with 50% aqueous trifluoroacetic acid gave 3-(2-azidoethyl)-3-deoxy-~-ribose(6) as a mixture of lactols (86% yield); hydrogenation of (6) in aqueous methanol in the presence of 10% palladium on carbon at 50 "C and 250 p.s.i. caused intramolecular reductive amination to give, after protection of the amino function via benzyl chloroformate, the carbamate (7),[a];' -2.1" (c, 1.0in CHCl,), in 62% yield.Selective esterification of the primary hydroxy group in the trio1 (7) by methanesulphonyl chloride in pyridine at -30 "C gave the primary mesylate (8),[~l];' +8.5" (c, 1.0 in CHCl,) in 61% yield. Hydrogenation of (8) gave the amino mesylate (2); however, treatment of (2) with sodium acetate gave intramolecular cyclisation by a hydroxy group- rather than by the piperidine nitrogen-to give a tetrahy-drofuran. Accordingly, compound (2) was converted into the bis-silyl ether (9) by treatment with t-butyldimethylsilyl trifluoromethanesulphonate in the presence of 2,6-lutidine (86% yield). Removal of the benzyloxycarbonyl protecting group by hydrogenolysis of (9) in the presence of palladium black, followed by cyclisation catalysed by sodium acetate, afforded the quinuclidine bis-silyl ether (lo), m.p.64-66 "C, [a];' zero (c, 1.0 in CHCl,), in 88% yield. Removal of the silyl protecting groups with aqueous trifluoroacetic acid gave (1a,3a,4a,5a)-quinuclidine-3,5-dioI (l), which sublimes above 205 "C, [a]:' zero (c, 0.5 in H20),in 64%yield [17% overall yield from (4)]. The 'H n.m.r. spectrum (DzO) of (1)t is very much simpler than that of the chiral quinuclidine-3,5-diol reported in the accompanying paper and "C n.m.r. spectrum (D20) of (1) shows only five non-equivalent carbons: Sc 9.1 (t, C-S), 33.3 (d, C-4), 44.3 (t, C-7), 52.7 (t, C-2 and C-6), and 63.5 (d, C-3 and C-5). The alternative synthesis of compound (1) from the azido alcohol (4) involves initial closure of the nitrogen function onto * Satisfactory microanalytical and spectral data have been obtained for all new compounds reported in this paper.t 6,, 1.58 (m, 2 H, 8-H and 8'-H), 1.87 (quin., 1 H, 4-H, J 3.1 Hz), 2.27 (m, 2 H, 2-H and 6-H), 2.64 (m, 2 H, 7-H and 7'-H), 2.82 (m, 2 H, 2'-H and 6'-H), and 3.78 (m, 2 H, 3-H and 5-H). 1068 J. CHEM. SOC. PERKIN TRANS. I 1989 HO CHO C-5 of the sugar. Esterification of the primary hydroxy function in (4) with methanesulphonyl chloride gave the corresponding azidomesylate (83% yield) which on hydrogenation in ethanol in the presence of 10% palladium on carbon, followed by sodium acetate-catalysed cyclisation and subsequent reaction CH20H with benzyl chloroformate, afforded the fully protected piper- idine (12), m.p.79-81 "C (lit.,3 79-81 "C), (66% yield) (51 (61 which with ethanethiol in aqueous trifluoroacetic acid gave the dithioacetal (13), m.p. 104--105"C, [a];' -48" (c, 1.0 in CHCl,) (92% yield). Sequential dibenzylation, mercuric chloride-catalysed hydrolysis, sodium borohydride reduction, and mesylation gave the mesylate (14) in 52% overall yield. Selective hydrogenolysis of the carbamate protecting group in (14) in the presence of palladium black in ethanol followed by cyclisation of the resulting amino mesylate in the presence of Z sodium acetate gave the dibenzylquinuclidine (11) in 64% yield. Subsequent hydrogenolysis of the dibenzyl ether (11) in the (71 R' = $ = H (81 R1 = H;R2 = MS (9)R' = ISil;R2 = Ms (11R=H (101R = ISil (111R = Bn presence of palladium black in acetic acid gave the meso-quinuclidienediol (l),identical with the diol (l),prepared above, in 81% yield [14% overall yield from (4)]. Acknowledgements A Fleming Fellowship from M.E.C./British Council (to J.A. S.) and a C.A.S.E. postgraduate studentship (to C. J. M.) in support of this work are gratefully acknowledged. Help from Dr Mike Williams of Pfizer Central Research with the nomenclature of quinuclidines is acknowledged. . Z References (12I (131 1 P. L. Stotter, M. D. Friedman, G. 0. Dorsey, R. W. Shiely, R. F. Williams, and D. E. Winter, Heterocycles, 1987, 25,251; P. L. Stotter, K. A. Hill, and M. D. Friedman, ibid., p. 259 and references cited therein. Ms = SOpMe 2 G. W. J. Fleet, K. James, and R. J. Lunn, Tetrahedron Lett., 1986,27, 2053. [Si 1 = SiBu' Me 2 Bn = CH2Ph Z = COpCHZPh 3 G. W. J. Fleet, K. James, R. J. Lunn, and C. J. Mathews, Tetrahedron 4 G. W. J. Fleet, C. J. Mathews, J. A. Seijas, M. P. Vazquez Tato, and D. Lett., 1986, 27, 3057. Brown, preceding communication. Received 28th November 1988; Paper 8/04691C
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